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Title: Acute coronary syndromes, platelets and the endothelium
Author: Rossington, Jennifer Ann
ISNI:       0000 0004 9350 0417
Awarding Body: University of Hull and the University of York
Current Institution: University of Hull
Date of Award: 2019
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Background: Acute coronary syndromes (ACS) are medical emergencies. Platelet and endothelial function are fundamental to the pathophysiology; and implicated in secondary conditions such as no reflow (NR). Guidelines support the administration of P2Y12 antagonists in ACS treatment, but the broader effects are unclear. Objectives: 1) Assess the impact of P2Y12 inhibition (ticagrelor) on the platelet sensitivity to prostacyclin (PGI2) and nitric oxide (NO) in coronary artery disease (CAD). 2) Review NR and identify at risk patients 3) Outline the optimal P2Y12 antagonist in ACS patients with diabetes. Methods: 1) Platelet and endothelial function assessed at baseline and after 3 days oral ticagrelor in CAD patients. Multiple aspects of platelet activation and sensitivity to PGI2 and NO were examined by flow cytometry. 2) Prospective case-control study of STEMI patients with and without NR. Multiple regression identified independent predictors and a risk score established. 3) Meta-analysis of randomised trials with clinical outcomes for P2Y12 inhibitors in ACS patients with diabetes. Results: Ex vivo studies of CAD patients (n=63) demonstrated that oral ticagrelor induced only modest platelet inhibition in whole blood. However, it enhanced the inhibitory actions of PGI2 and NO. Ticagrelor potently amplified PGI2 inhibition of platelet-leukocyte aggregate formation (a measure of platelet inflammatory function). Ticagrelor improved endothelial reactive hyperaemic index (RHI), which correlated with platelet sensitivity. 24(13.9%) STEMI patients suffered NR, which significantly increased the risk of cardiovascular death. The independent predictors of NR were lesion complexity, systolic hypertension, weight < 78kg, and history of hypertension. Systematic review of 7 studies, established newer P2Y12 antagonists (ticagrelor and prasugrel) were optimal for ACS patients with diabetes; with a trend to prasugrel superiority in the reduction of major adverse cardiovascular events. Conclusion: In patients with CAD, P2Y12 antagonism by ticagrelor promotes inhibition of platelet haemostatic and inflammatory function by endogenous regulators; and improves endothelial function.
Supervisor: Hoye, Angela ; Naseem, Khalid Sponsor: AstraZeneca
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine